Plasma Gut Microbe-Derived Metabolites Associated with Peripheral Artery Disease and Major Adverse Cardiac Events
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Population
2.2. Variables
2.3. Endpoints
2.4. Detection and Quantification of Metabolites by High-Performance Liquid Chromatography–Tandem Mass Spectrometry (LC-MS/MS)
2.5. Statistical Analysis
3. Results
3.1. Study Population
3.2. Correlation between Metabolites and ABI
3.3. Relationship between Metabolites and MACE
4. Discussion
5. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Covariates N (%) or Median [Interquartile Range] | Control Cohort (N = 37) | Claudication (N = 119) | p Value |
---|---|---|---|
Age | 67 (60–74) | 68 (65–73) | 0.19 |
Male sex | 32 (86.5) | 115 (96.6) | 0.02 |
African-American | 7 (18.9) | 23 (19.3) | 0.54 |
Body mass index (kg/m2) | 29.4 (26.1–31.3) | 27.8 (24.4–31.2) | 0.18 |
Coronary artery disease | 0 | 47 (39.5) | <0.0001 |
Prior coronary revascularization | 33 (75%) | ||
Prior MACE | 0 | 46 (42.4) | <0.0001 |
Hypertension | 25 (67.6) | 111 (93.3) | <0.0001 |
Hyperlipidemia | 24 (64.9) | 100 (84) | <0.01 |
Diabetes mellitus | 8 (21.6) | 41 (34.5) | 0.14 |
Current/former smoker | 27 (75) | 119 (93.3) | 0.002 |
Aspirin use | 19 (51.4) | 86 (72.3) | 0.02 |
Statin use | 23 (62.2) | 95 (79.3) | 0.03 |
ABI | 1.1 (1.1–1.2) | 0.73 (0.64–0.81) | <0.0001 |
Total cholesterol, mg/dL | 170 (142.5–197) | 158 (127–182) | 0.10 |
LDL cholesterol, mg/dL | 99 (79.5–124.5) | 82 (60–106) | 0.008 |
HDL cholesterol, mg/dL | 43.5 (38–47.5) | 42 (35–55) | 0.89 |
eGFR, mL/min/1.73 mm2 | 82 (66–107) | 70.5 (60.5–86.5) | 0.02 |
hs-CRP, mg/mL | 3.3 (1.2–5.1) | 2.4 (1.5–6) | 0.82 |
Rutherford classification | <0.0001 | ||
0 | 37 (100) | 4 (3.4) | |
1 | 0 | 38 (32.5) | |
2 | 0 | 34 (29.1) | |
3 | 0 | 41 (35.0) | |
Metabolites, μmol | |||
Indole derivatives | |||
Serotonin | 1.3 (.52–2.4) | 0.96 (0.48–1.38) | 0.02 |
KYN | 3.8 (2.9–5) | 2.3 (1.9–4.2) | 0.0001 |
TRP | 0.076 (0.047–0.099) | 0.052 (0.038–0.076) | 0.005 |
KYN/TRP ratio (x100) | 4975 (3717–6783) | 4935 (3949–6743) | 0.69 |
IPA | 2.7 (1.7–4.1) | 1.07 (0.57–1.86) | <0.0001 |
I3A | 0.21 (0.14–0.24) | 0.12 (0.10–0.16) | <0.0001 |
IS | 1.3 (0.6–2.4) | 2.8 (1.8–4.9) | 0.002 |
HAA | 0 | 0.31 (0.22–0.54) | <0.0001 |
Phenyl derivatives | |||
PCS | 0.23 (0.13–0.37) | 0.31 (0.19–0.51) | 0.07 |
HA | 18.4 (11.7–24.2) | 9.4 (6.3–16.7) | <0.0001 |
Cytokines, pg/mL | |||
IL-6 | 0.85 (0.63–1.23) | 1.2 (0.93–1.81) | 0.02 |
ICAM | 206 (172–300) | 246 (207–300) | 0.06 |
TNF-α | 1.7 (1.3–2.0) | 1.98 (1.64–2.35) | 0.004 |
Omega-3 index | 0.064 (0.050–0.072) | 0.046 (0.040–0.055) | <0.0001 |
Metabolite | OR | 95% CI | p Value |
---|---|---|---|
ln serotonin | 0.69 | 0.45–1.1 | 0.1 |
ln KYN | 0.22 | 0.086–0.57 | 0.002 |
ln TRP | 0.69 | 0.34–1.4 | 0.29 |
ln KYN/TRP | 0.65 | 0.36–1.15 | 0.14 |
ln HA | 0.42 | 0.24–0.72 | 0.002 |
ln IPA | 0.36 | 0.21–0.61 | 0.0002 |
ln IS | 1.8 | 1.11–3.00 | 0.02 |
ln PCS | 1.1 | 0.72–1.72 | 0.63 |
ln HAA | 4.44 | 2.6–7.5 | <0.0001 |
ln I3A | 0.11 | 0.03–0.35 | 0.0002 |
Variable | No MACE N = 111 (79.9%) | MACE N = 28 (20.1%) | p Value |
---|---|---|---|
Age | 67.4 (63.6–73.3) | 68.8 (64.4–75.8) | 0.35 |
Male sex | 108 (97.3%) | 27 (96.4%) | 0.99 |
African-American | 24 (21.6%) | 4 (14.3%) | 0.56 |
Body mass index (kg/m2) | 28.6 (25.0–31.2) | 27.8 (24.6–32.6) | 0.99 |
Past medical history | |||
Coronary artery disease | 27 (24.3%) | 17 (60.7%) | 0.0002 |
Prior coronary revascularization | 18 (66.7%) | 15 (88.2%) | 0.11 |
Prior MACE | 29 (26.1%) | 17 (60.7%) | 0.0005 |
Hypertension | 98 (88.3%) | 25 (89.3%) | 0.88 |
Hyperlipidemia | 92 (82.3%) | 22 (78.6%) | 0.60 |
Diabetes mellitus | 35 (31.5%) | 10 (35.7%) | 0.67 |
Current/former smoker | 100 (90.9%) | 25 (89.3%) | 0.79 |
Aspirin use | 76 (68.5%) | 20 (71.4%) | 0.76 |
Statin use | 82 (73.9%) | 23 (82.1%) | 0.36 |
ABI | 0.8 (0.7–1.0) | 0.7 (0.6–0.8) | 0.01 |
Total cholesterol, mg/dL | 160 (136–185) | 156 (122–189.5) | 0.61 |
LDL cholesterol, mg/dL | 83 (64–110) | 83 (57.5–108.5) | 0.53 |
HDL cholesterol, mg/dL | 43 (36–54) | 45 (35.5–50.5) | 0.57 |
eGFR, mL/min/1.73 mm2 | 73 (63–90) | 72 (60–93) | 0.76 |
hs-CRP, mg/mL | 2.4 (1.3–5.1) | 3.4 (1.7–7.1) | 0.28 |
Rutherford classification | 0.08 | ||
0 | 29 (26.4%) | 4 (14.3%) | |
1 | 30 (27.3%) | 4 (14.3%) | |
2 | 25 (22.7%) | 7 (25.0%) | |
3 | 26 (23.6%) | 13 (45.4%) | |
Metabolites, μmol | |||
Indole derivatives | |||
Serotonin | 0.96 (0.40–1.49) | 1.14 (0.64–1.51) | 0.46 |
KYN | 2.84 (2.02–4.57) | 2.89 (1.77–3.21) | 0.02 |
TRP | 0.06 (0.04–0.09) | 0.04 (0.029–0.057) | 0.003 |
KYN/TRP ratio (x100) | 4790 (3798–6491) | 4955 (4189–6892) | 0.30 |
IPA | 1.15 (0.61–2.3) | 1.11 (0.63–1.77) | 0.65 |
I3A | 0.14 (0.11–0.20) | 0.11 (0.096–0.16) | 0.02 |
IS | 2.70 (1.55–4.56) | 3.03 (1.81–4.40) | 0.74 |
HAA | 0.26 (0–0.44) | 0.28 (0.11–0.63) | 0.32 |
Phenyl derivatives | |||
PCS | 0.29 (0.17–0.47) | 0.32 (0.21–0.70) | 0.20 |
HA | 11.0 (7.1–19.7) | 9.1 (5.3–16.8) | 0.12 |
Cytokines, pg/mL | |||
IL-6 | 1.1 (0.79–1.49) | 1.5 (1–2.4) | 0.03 |
ICAM | 230 (196.4–280) | 272.9 (221.5–308.1) | 0.07 |
TNF-α | 1.86 (1.45–2.24) | 2.05 (1.82–2.31) | 0.04 |
Omega-3 index | 0.07 (0.06–0.08) | 0.05 (0.04–0.06) | 0.49 |
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Ho, K.J.; Ramirez, J.L.; Kulkarni, R.; Harris, K.G.; Helenowski, I.; Xiong, L.; Ozaki, C.K.; Grenon, S.M. Plasma Gut Microbe-Derived Metabolites Associated with Peripheral Artery Disease and Major Adverse Cardiac Events. Microorganisms 2022, 10, 2065. https://doi.org/10.3390/microorganisms10102065
Ho KJ, Ramirez JL, Kulkarni R, Harris KG, Helenowski I, Xiong L, Ozaki CK, Grenon SM. Plasma Gut Microbe-Derived Metabolites Associated with Peripheral Artery Disease and Major Adverse Cardiac Events. Microorganisms. 2022; 10(10):2065. https://doi.org/10.3390/microorganisms10102065
Chicago/Turabian StyleHo, Karen J., Joel L. Ramirez, Rohan Kulkarni, Katharine G. Harris, Irene Helenowski, Liqun Xiong, C. Keith Ozaki, and S. Marlene Grenon. 2022. "Plasma Gut Microbe-Derived Metabolites Associated with Peripheral Artery Disease and Major Adverse Cardiac Events" Microorganisms 10, no. 10: 2065. https://doi.org/10.3390/microorganisms10102065